Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 13, Issue 3, Pages 827-841Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2021.12.003
Keywords
Steatosis; Gut Microbiota; Lipid Metabolism; Peroxisome Proliferator-Activated Receptor alpha
Categories
Funding
- National Key R&D Program of China [2017YFC0908903]
- National Natural Science Foundation of China [81873565, 81470840, 81700503]
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The expansion of Escherichia-Shigella in NAFLD patients was found to be associated with disease severity, independent of obesity. Escherichia fergusonii induced nonobese NAFLD in rats characterized by hepatic steatosis and hepatocyte ballooning, disrupting host lipid metabolism. Additionally, E fergusonii-derived msRNA 23487 down-regulated host hepatic peroxisome proliferator-activated receptor alpha expression, contributing to liver lipid accumulation.
BACKGROUND & AIMS: Gut microbiota and microbial factors regulate the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in patients with obesity and metabolic abnormalities, but little is known about their roles in nonobese NAFLD. Expansion of Escherichia is associated with NAFLD pathogenesis. We aimed to investigate the pathogenic role of Escherichia fergusonii and its products in the development of nonobese NAFLD. METHODS: We characterized the intestinal microbiome signature in a cohort of NAFLD patients and healthy controls by 16S ribosomal RNA sequencing. The role of E fergusonii was estimated in rats after 16 weeks of administration, and features of NAFLD were assessed. E fergusonii-derived microRNA-sized, small RNAs (msRNAs) were analyzed by deep sequencing. RESULTS: We detected an expansion of Escherichia_Shigella in NAFLD patients compared with healthy controls, and its increase was associated with disease severity independent of obesity. E fergusonii, a member of the genus Escherichia, induced the development of nonobese NAFLD characterized by hepatic steatosis and hepatocyte ballooning in rats without obesity. It disturbed host lipid metabolism by inhibiting hepatic lipid beta-oxidation and promoting de novo lipogenesis. We also showed that E fergusonii caused the development of hepatic inflammation and fibrosis in a sizable fraction of animals at an advanced stage of NAFLD. Mechanistically, E fergusonii-derived msRNA 23487 down-regulated host hepatic peroxisome proliferator-activated receptor alpha expression, which could contribute to lipid accumulation in the liver. CONCLUSIONS: These results suggest that E fergusonii promotes the pathogenesis of steatohepatitis and fibrosis in non-obese rats by secreting msRNA 23487, and it might be a potential biomarker for predicting steatohepatitis in nonobese NAFLD.
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